DE102021112136A1 - Process and device for the production of microneedle elements and microneedle elements - Google Patents

Abstract

A method for producing microneedle elements (22, 23), with the steps: providing a mold element (10) for the microneedle elements (22, 23) to be produced, filling the mold element (10) with a first formulation (20), curing the first formulation (20), and pressurizing the first formulation (20) during curing. Furthermore, a microneedle element (22, 23) and a device (100) for producing microneedle elements (22, 23).

Description

The invention relates to a method and a device for producing microneedle elements having at least one microneedle and a microneedle element

Microneedle elements such as, for example, microarrays have a multiplicity of microneedles, which are usually arranged in or connected to a carrier element, such as in a patch, a plaster or the like. On the other hand, it can be For example, a microneedle element can also be a single microneedle or a plurality of individual microneedles. In general, microarrays have a large number of microneedles, the length of which is dimensioned such that when they are pressed into the skin of a patient, they penetrate the skin only far enough so that nerves and vessels are not touched by the needle tips, if possible. In this case, the needles have an active substance, for example a drug. The corresponding active substance can, for example, be applied to an upper side of the needle or arranged in the needles. When the agent is placed in the needles, the needles or parts of the needles are generally made of a material which is soluble in the patient's skin. Dissolving microneedles can, in particular, have one or more active substance-containing and/or active substance-free formulations, preferably consist of them.

Microneedles and/or microarrays are produced, for example, with the aid of matrices which have a large number of shaped openings designed as depressions. These mold openings serve as negative molds for the microneedles to be produced and/or the microarray to be produced.

A conventional manufacturing process for microneedle elements is in 1a-1f shown. 2 shows a detailed view 1f (II) . The starting point is a matrix 10, e.g. a silicone matrix, as in 1a shown. The mold openings 12 of the matrix 10 are first filled with a liquid formulation 14, also known as a tip formulation, which in particular has an active ingredient ( 1b ). This results in filling of the tips of the mold openings 12 ( 1c ) with the formulation 14. Curing then takes place by drying the tip formulation 14, so that tips (tips) 16 of the microneedles to be produced are formed. Due to the drying, there is a reduction in volume, in particular due to a reduction in a solvent, such as e.g. B. water and / or ethanol, the formulation. Due to the volume reduction, as in 1d shown, result in an uneven, e.g. concave, surface 18 of the tip formulation 14. After the tip formulation 14 has hardened, the mold openings 12 are filled further with a further formulation 20, which is in particular free of active ingredients, also called a backing formulation ( 1e ). The backing formulation 20 is then cured, in particular by drying. The backing formulation 20 and the tip formulation 14 are bonded. The bonded, cured formulations 14, 20 together form a microneedle 22' ( 1f ). The microneedles 22' can be removed from the mold, for example by means of an adhesive foil. When filling with the backing formulation 20, air inclusions 24' frequently occur between the backing formulation 20 and the tip formulation 14. The illustrations in the figures are schematic. For example, the drop-shaped formulations 14, 20 are in 1b and 1e may not be shown so large that a corresponding filling (according to 1c and 1f ) would exist. The filling by means of individual drops can also only be seen schematically. For example, filling with several drops and/or a jet of formulation is also possible. For example, an inflowing filling is also possible instead of or in addition to the dripping filling shown.

These air pockets 24' (see e.g. 2 ) can lead to several problems. On the one hand, there may be no or insufficient connection between the backing formulation 20 and the tip formulation 14 . On the other hand, instabilities can be present, so that breaking occurs, for example, during demolding, handling or use.

The object of the invention is to create a method and a device for producing microneedle elements having at least one microneedle, the quality, in particular the stability, of the microneedle elements to be produced being improved. A further object of the invention is to create a microneedle element whose quality, in particular its stability, is improved.

The objects are achieved according to the invention by a method according to claim 1, a device according to claim 13, and a microneedle element according to claim 12.

The method according to the invention is a method for producing microneedle elements, wherein a microneedle element to be produced has at least one microneedle. The method according to the invention is preferably in particular a method for producing microarrays, the microneedle element to be produced being a microarray which connects a plurality of microneedles, in particular by means of a carrier element are, has. On the other hand, it is also possible that the method according to the invention is a method for producing, in particular individual, microneedles. A first step of the method consists in providing a mold element for the microneedle elements to be produced. The shaped element is in particular a matrix, for example one containing silicone. The mold element preferably has at least one mold opening designed as a negative mold for the microneedle element to be produced. A further step of the method consists in filling the mold element with a first formulation, in particular a backing formulation. After the mold element has been filled with the first formulation, the first formulation is cured. At least partially simultaneously with curing, the first formulation is pressurized during curing. It is preferred that the filling with the first formulation takes place in such a way that the mold opening is essentially completely filled with formulation. Due to the application of pressure during curing, it is particularly advantageously possible for gas inclusions, for example air inclusions, to escape from the formulation and/or no gas inclusions to be introduced. Thus, in particular, a more stable microneedle element can be produced. It is preferred that the mold openings are cylindrical or conical. In particular, the base of the cylindrical or conical mold opening is a circle, oval, rectangle or square. If the mold opening has a cone shape, it can also be a truncated cone. The cross-section of the mold opening is preferably tapered. In particular, the mold openings are symmetrical in the longitudinal direction, in particular rotationally symmetrical.

It is possible that only a single formulation is introduced, which thus in particular forms the entire microneedle element to be produced. However, it is preferred that the microneedle element to be produced is produced from several, in particular at least two, formulations. It is therefore preferred that before filling with the first formulation, the mold element is filled with a second formulation, in particular a tip formulation. The following is preferably implemented, in particular in the following order: i. providing the mold element; ii. filling the mold element with the second formulation; iii. filling the mold element with the first formulation; IV. curing while pressurizing the first and preferably the second formulation. By curing the first formulation with simultaneous pressurization, it can thus be advantageously implemented that gas inclusions, for example air inclusions, can escape between the first and second formulation. Additionally or alternatively, it is particularly advantageous that gas inclusions between the first and second formulation are compressed, preferably compacted. In particular, the compression means that gas inclusions, such as air bubbles, are smaller. After curing, it is generally no longer possible for the gas inclusions to expand. This has the advantage that there is a better connection, in particular a larger connection surface, between the first and second formulation.

In a preferred embodiment, after the mold element is filled with the second formulation and in particular before the mold element is filled with the first formulation, the second formulation is cured. It is possible that pressure is applied at the same time as the second formulation is cured.

It is possible that more than two formulations are used to produce the microneedle element. Thus, in a preferred embodiment of the method, before the step of filling the shaped element with the first formulation and after the step of filling the shaped element with the second formulation, the further step is carried out at least once: filling the shaped element with at least one additional formulation, in particular an intermediate formulation, and preferably curing the at least one additional formulation, preferably with simultaneous application of pressure.

It is preferred that the first and/or the second and/or the at least one additional formulation comprises a solvent such as water and/or liquid organic substances and/or alcohol, preferably ethanol. In particular, the second formulation has at least one active ingredient. The first and/or the at least one additional formulation is preferably free of active ingredient.

In a preferred embodiment, when the shaped element is filled with the first formulation, the shaped element is overfilled, so that the first formulation emerges from the shaped element. The overfill can then be removed or remain. If the overfill remains, it is possible to create a backing layer, for example.

It is preferred that the first and/or the second and/or the at least one additional formulation is cured by drying, in particular air drying. Curing is preferably drying. It is possible that the drying takes place by means of an air stream and/or infrared.

In a preferred embodiment, temperature is introduced during the curing of the first and/or the second and/or the at least one additional formulation.

It is preferred that the pressurization, in particular of the first and/or the second and/or the at least one additional formulation, takes place by means of excess pressure. In this context, excess pressure preferably means a gas pressure above ambient pressure. It is preferred that the overpressure is generated by means of an overpressure chamber, with the shaped element being arranged at least partially, in particular completely, within the overpressure chamber. In particular, the excess pressure is at least 1 bar, preferably at least 3 bar and particularly preferably at least 3 bar above the ambient pressure. In a preferred embodiment, the overpressure does not exceed 10 bar, in particular not 5 bar. As an alternative or in addition to the application of pressure by means of excess pressure, the application of pressure can take place by means of a pressing device having a stamp and/or a roller.

In a preferred embodiment, the application of pressure and/or the curing, in particular of the first and/or the second and/or the at least one additional formulation, takes place over a period of at least 30 minutes, preferably at least 60 minutes, particularly preferably at least 90 minutes.

In particular, the mold element has a plurality of microneedle negative molds. The multiple negative microneedle molds form, in particular, a negative microarray mold.

It is preferred that the mold element is filled with the first formulation in such a way that the first formulation covers the multiple microneedle negative molds. In this way, a carrier element, also known as a backing, can advantageously be formed integrally with the first formulation.

The microneedle element according to the invention is in particular a microneedle or a microarray having at least one microneedle. The microneedle element can be obtained in particular by the method according to the invention described above. As an alternative or in addition to the definition that the microneedle element can be obtained by the method described above, the microneedle element according to the invention has at least two, preferably at least partially cured, formulations. The formulations are linked. In particular, at least one tip formulation and one backing formulation are involved. At least one gas inclusion, for example an air bubble, is preferably arranged between the at least two formulations. The gas inclusion is above the ambient pressure. Preferably there is overpressure between the formulations. The pressure between the formulations, in particular the pressure of the at least one gas inclusion, is preferably at least 2 bar, particularly preferably at least 3 bar. In a preferred embodiment, the microneedle element has a cavity, preferably essentially spherical or ellipsoidal, between the first and second formulation. The cross-sectional area of the cavity is preferably smaller than the connecting area between the first and second formulation, in particular by at least 30%. The diameter of the cavity is in particular smaller than the diameter of the microneedle element at the connection point between the first and second formulation, in particular by at least 30%. It is particularly advantageous that the cavity of the microneedle element according to the invention is smaller than in previous microneedle elements. Furthermore, it is implemented particularly advantageously that the microneedle element according to the invention has an essentially spherical cavity, preferably with a circular cross section, with previous microneedle elements having an ellipsoidal cavity.

The device according to the invention is a device for producing a microneedle element having at least one microneedle. The device has a mold element for the microneedle elements to be produced. The shaped element is designed in particular like the shaped element described above for the method according to the invention. Furthermore, the device has a pressurization device. The pressurization device preferably has an overpressure chamber and/or a pressing device. The pressurization device preferably has a pump for generating excess pressure, in particular in the excess pressure chamber. In a preferred embodiment, the device has a drying device, in particular one that generates heat and/or an air flow. The drying device can be connected to the pressurization device, in particular in one piece. The pressure application device is preferably designed and/or arranged in such a way that pressure is applied to the shaped element. In particular, the pressure is applied at least to the mold openings of the mold element. The drying device can have a pump and/or a heating element, preferably one that generates infrared. It is preferred that the device has a filling device, preferably having a dosing device, for filling the mold element with at least one formulation.

The device is designed in particular to carry out the method according to the invention described above. The device preferably has one or more of the features described above in the context of the method, in particular the device features there.

The invention is explained in more detail below on the basis of a preferred embodiment with reference to the accompanying drawings.

• 1a-1f schematisch geschnittene Seitenansichten einer Matrize in verschiedenen Zuständen zur Darstellung eines Verfahrens zur Herstellung von Mikronadelelementen gemäß dem Stand der Technik,
• 2 eine Detailansicht gem. II aus 1f zur Darstellung eines Mikronadelelements in Form einer Mikronadel des Stands der Technik,
• 3 eine schematisch geschnittene Seitenansicht einer Matrize in einem Zustand zur Darstellung einer Ausführung eines erfindungsgemäßen Verfahrens zur Herstellung von Mikronadelelementen,
• 4 eine Detailansicht gem. IV aus 3 zur Darstellung einer Ausführungsform eines erfindungsgemäßen Mikronadelelements in Form einer Mikronadel,
• 5-6 schematisch geschnittenen Seitenansichten einer Matrize in einem Zustand zur Darstellung weiterer Ausführungen eines erfindungsgemäßen Verfahrens zur Herstellung von Mikronadelelementen mit weiteren Ausführungsformen erfindungsgemäßer Mikronadelelemente, und
• 7-9 schematisch geschnittenen Seitenansichten von Ausführungsformen erfindungsgemäßer Vorrichtungen zur Herstellung eines Mikronadelelements, mit einer Matrize in einem Zustand zur Darstellung weiterer Ausführungen eines erfindungsgemäßen Verfahrens zur Herstellung von Mikronadelelementen.

Show it:

• 1a-1f Schematically sectional side views of a die in different states to illustrate a method for producing microneedle elements according to the prior art,
• 2 a detailed view according to II 1f for the representation of a microneedle element in the form of a microneedle of the prior art,
• 3 a schematically sectional side view of a die in a state for representing an embodiment of a method according to the invention for the production of microneedle elements,
• 4 a detailed view according to IV 3 to illustrate an embodiment of a microneedle element according to the invention in the form of a microneedle,
• 5-6 Schematically sectioned side views of a die in a state for showing further embodiments of a method according to the invention for the production of microneedle elements with further embodiments of microneedle elements according to the invention, and
• 7-9 Schematically sectioned side views of embodiments of devices according to the invention for producing a microneedle element, with a die in a state for showing further embodiments of a method according to the invention for producing microneedle elements.

Similar or identical parts or elements are identified in the figures with the same reference numerals or variations thereof (e.g. 22 and 22). In order to improve clarity in particular, elements that have already been identified are preferably not provided with reference numbers in all figures.

the 1a-1f and 2 are already described above.

the 3 based on the 1a-1f . Shown here is a on the in 1f shown state following state, however (in 1f ) the backing formulation 20 has not yet hardened and/or dried.

The backing formulation 20 that has not yet hardened, in particular when it is moist, is pressurized ( 3 ). This pressure can be applied by means of physical pressure, e.g. by means of a stamp (cf. 8th ) or by means of a roller. Pressurization by means of excess pressure, e.g. by means of an excess pressure chamber (cf. 7 ). The overpressure is in particular about 3 bar compared to the ambient pressure. The application of pressure takes place at the same time as the backing formulation 20 is cured. The application of pressure preferably takes place for at least 30 minutes. Thus, pressure is applied to the backing formulation 20 over a period of time.

Due to the applied pressure, the air pocket is compressed, causing it to 3 is an air bubble. The air bubble forms a cavity 24 between the backing formulation 20 and the tip formulation 14 . When the backing formulation 20 hardens, in particular when it dries, the air bubble can no longer expand. A detailed view of this is in 4 shown.

Due to the compression, the air bubble and thus the cavity 24 is significantly smaller than the cavities 24' of previous production methods (cf. e.g. 2 ). This results in a greater connection contact between the backing formulation 20 and the tip formulation 14 than with previous manufacturing processes (cf. e.g. 2 ). The cross-sectional area of the cavity 24 is preferably smaller than the connecting area between the backing formulation 20 and the tip formulation 14, in particular by at least 30%. The diameter of the cavity is in particular smaller than the diameter of the microneedle 22 at the connection point between the backing formulation 20 and the tip formulation 14, in particular by at least 30%. This minimized cavity 24 and the increased connecting contact between the backing formulation 20 and the tip formulation 14 advantageously result in increased stability of the microneedle 22 compared to previous microneedles 22' (cf. e.g. 2 ).

The air pressure in the cavity 24 corresponds in particular to the overpressure applied. The air pressure in the cavity 24 is preferably higher than the ambient pressure. The air pressure in the cavity 24 is in particular higher than the air pressure in the cavity 24' of the prior art (cf. e.g. 2 ).

The microneedles 22 of 3 and 4 correspond to an embodiment of microneedle elements according to the invention, wherein several, esp discard all microneedles 22 3 preferably correspond to a microarray according to the invention.

5 is essentially based on 3 . In contrast to the version from 3 indicates the microarray 23 5 Microneedles 22 with three formulations 14, 20, 26 on. Here, the cavities 24, 28 are each miniaturized (compared to the prior art).

These small cavities 24, 28 can be implemented, for example, by applying pressure twice separately with simultaneous curing, or by applying pressure together and curing the formulations 20, 26 at the same time.

6 is also essentially based on 3 . In contrast to the version from 3 indicates the microarray 23 is used 6 a one-piece microarray 23. This can be implemented in particular by overfilling the mold openings 12 with backing formulation 20, so that the backing formulation 20 connects for a plurality of microneedles 22 to be produced. In this case, this connection surface serves, for example, as a backing layer 21 for the microarray 23. Pressurization according to the above definition can be applied to the common backing formulation 20 of the plurality of microneedles 22 to be produced.

7 is also essentially based on 3 . Next to the filled form element 10 is in 6 a device 100 for producing a microneedle element 23 is shown.

The device 100 has a pressurization device 30 . The pressurization device 30 has a chamber 34 , in particular an overpressure chamber, with a chamber wall 35 . The chamber 34 encloses the shaped element 10 at least partially, in particular completely. An overpressure can be applied to the backing formulation 20 via a pressure generator 36 connected to the chamber 34, in particular a pump. The pressure is applied via line 46 as shown.

Optionally, the device (as shown) can have a drying device 38 . The drying device 38 shown has an air flow generator 40 . The air flow generator 40 can in particular have a pump and/or a heating element. The drying device is shown as being connected to the chamber 34 via the supply line 42 and the discharge line 44. The drying device 38 can be used, for example, to generate a particularly warm air flow for drying the backing formulation 20.

The device 100 off 8th essentially corresponds to the device 100 7 , wherein another embodiment of the drying device 38 is shown. The drying device 38 shown is a heating element. Here, the backing formulation is heated. This can be done, for example, via a heating device 48 that generates infrared rays 50 and that is arranged, for example, in the chamber 34 .

7 is also essentially based on 3 . A further embodiment of the device 100 for producing a microneedle element 23 is shown.

The pressure application device 30 is a pressing device here. The pressing device includes a ram 32 which applies physical pressure to the backing formulation.

Claims (13)

Method for producing microneedle elements (22, 23) having at least one microneedle, with the steps: - providing a mold element (10) for the microneedle elements (22, 23) to be produced, - Filling the mold element (10) with a first formulation (20), in particular a backing formulation, - curing the first formulation (20), and - pressurizing the first formulation (20) during curing. procedure after claim 1 , characterized in that before the step of filling the mold element (10) with the first formulation (20), the method has the further step: - Filling the mold element (10) with a second formulation (14), in particular a tip formulation. procedure after claim 2 , characterized in that the method after the step of filling the mold element (10) with the second formulation (14) has the further step: - curing of the second formulation (14), in particular with simultaneous application of pressure. procedure after claim 3 , characterized in that the method before the step of filling the mold element (10) with the first formulation (22) and after the step of filling the mold element with the second Formulation (14) has the further step: - filling the mold element with at least one additional formulation (26), in particular an intermediate formulation, and preferably - curing the at least one additional formulation (26), in particular with simultaneous pressurization. Procedure according to one of Claims 1 - 4 , characterized in that when the mold element (10) is filled with the first formulation, the mold element (10) is overfilled, so that the first formulation (20) emerges from the mold element (10). Procedure according to one of Claims 1 - 5 , characterized in that drying, in particular air drying, takes place during curing. Procedure according to one of Claims 1 - 6 , characterized in that temperature is introduced during curing. Procedure according to one of Claims 1 - 7 , characterized in that the pressure is applied by means of excess pressure and/or by means of a pressing device, in particular having a stamp (32) and/or a roller. Procedure according to one of Claims 1 - 8th , characterized in that the application of pressure and/or the curing takes place over a period of at least 30 minutes, preferably at least 60 minutes, particularly preferably at least 90 minutes. Procedure according to one of Claims 1 - 9 , characterized in that the mold element (10) has a plurality of negative microneedle molds, wherein the plurality of negative microneedle molds in particular form a negative microarray mold. Procedure according to one of Claims 1 - 10 , characterized in that the filling of the mold element (10) with the first formulation (20) takes place in such a way that the first formulation (20) covers the plurality of negative microneedle molds. Microneedle element (22, 23), in particular microneedle or microarray, obtainable by a method according to one of Claims 1 until 11 . Device (100) for the production of at least one microneedle having microneedle elements (22, 23), in particular by a method according to one of Claims 1 until 12 , wherein the device has: - a mold element for the microneedle elements (22, 23) to be produced, - a pressurization device (30), in particular having an overpressure chamber (34), and - preferably a drying device (30), in particular generating heat and/or an air flow 38), wherein the pressurization device (30) is designed in such a way that pressure is applied to the mold element (10).

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